Phase 1/2 Study to Evaluate the Safety and Efficacy of ATA188 in Subjects With Progressive Multiple Sclerosis

Secondary Progressive Multiple Sclerosis Clinical Trial

— EMBOLD  

Official title:

A Phase 1/2, Two-part, Open-label Dose-escalation and Double-blind, Placebo-controlled Dose-expansion Study With an Open-label Extension to Evaluate the Safety and Efficacy of ATA188 in Subjects With Progressive Multiple Sclerosis

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03283826
• Other study ID #: ATA188-MS-101
• Status: Terminated
• Phase: Phase 1/Phase 2
• Start date: October 19, 2017
• Est. completion date: January 17, 2024

Study information

• Verified date: February 2024
• Source: Atara Biotherapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to evaluate the safety and tolerability of ATA188 as a monotherapy in Parts 1 and 2, to determine the recommended Part 2 dose (RP2D) of ATA188 as monotherapy in Part 1, and to evaluate the effect of ATA188 treatment on clinical disability, as assessed by confirmed Expanded Disability Status Scale (EDSS) improvement at 12 months in Part 2 in participants with progressive forms of multiple sclerosis (MS) (primary progressive multiple sclerosis [PPMS] and secondary progressive multiple sclerosis [SPMS]).

Description:

This is a multicenter, 2 part study in adult participants with progressive forms of MS (PPMS/SPMS) with an open-label, single-arm, sequential dose-escalation period (Part 1) and a double-blind, randomized, placebo-controlled dose-expansion period (Part 2) followed by open-label extension (OLE) period. Part 2 and the OLE have been initiated by the sponsor's discretion based on a review of data from the dose-escalation cohorts. This study will evaluate the safety and efficacy of ATA188 administered by intravenous (IV) infusion. ATA188 will be selected for each participant based on matching 2 or more human leukocyte antigen (HLA) alleles shared between ATA188 and the participant, at least 1 of which is a HLA-restricting allele. In Part 1, participants received 2 cycles of ATA188 and entered 12 months follow-up period after the last dose of ATA188. Participants who completed at least the first year of the dose-escalation period and were active in the study have entered the OLE period. In OLE period, participants will receive the same RP2D assigned to Part 2 participants at the time of the Part 1 participant's first dose in each year of the OLE. In OLE period, participants will receive 1 cycle of ATA188 treatment every 12 months (Q12M) for up to 4 years (ie, Years 2 to 5). Otherwise, end of study (EOS) visit will be conducted at 24 months after Cycle 1 Day 1. In Part 2, participants will be randomized in 1:1 ratio to receive ATA188 at the RP2D or matching placebo, stratified by progressive MS diagnosis (PPMS vs SPMS) and any prior exposure to anti-CD20 therapy (yes vs no). Participants will receive 2 cycles of ATA188 at the RP2D or matching placebo and will be followed for at least 12 months after the first dose of study drug (ie, Year 1). In second year (Year 2), participants who received placebo in Year 1 will receive 2 cycles of ATA188 at the RP2D assigned at randomization and participants who received ATA188 at the RP2D in Year 1 will receive 1 cycle of ATA188 (at the RP2D assigned at randomization) and 1 cycle of placebo to maintain the blind. Participants who complete Year 2 will enter the OLE period to receive ATA188 Q12M for up to 3 years (ie, Years 3 to 5) at the RP2D that was last selected by the sponsor for Part 2. The end of study visit will be scheduled at 5 years (60 months) after the first dose of study drug (ie, Cycle 1 Day 1). Based on interim analysis, the recruitment for Parts 1and 2 have completed.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 134
• Est. completion date: January 17, 2024
• Est. primary completion date: November 9, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 60 Years

Eligibility

Inclusion Criteria:

• For Part 1: History of progressive forms of MS (PPMS or SPMS), as defined by the 2010 Revised McDonald criteria for the diagnosis of MS
• For Part 1: 18 to < 66 years of age
• For Part 1: EDSS scores of 3.0 to 7.0. Participants with EDSS scores of 6.5 to 7.0 must retain measurable upper limb function as assessed by the 9-hole Peg Test (9HPT).
• For Part 2: Current diagnosis of a progressive form of MS (PPMS or SPMS) as defined by the 2017 Revised McDonald criteria
• For Part 2:18 to < 61 years of age
• For Part 2:EDSS scores of 3.0 to 6.5
• Positive EBV serology
• Willing and able to provide written informed consent

Exclusion Criteria:

• Clinical relapse as follows: For Part 1: Active clinical relapse between providing informed consent and the first dose of study drug. For Part 2: Documented clinical and/or radiological relapse for 2 years prior to screening, including gadolinium (Gd)-enhancing lesion(s) on any brain MRI scans available during this period (A participant will also be considered ineligible if any clinical and/or radiological relapse is reported between screening and the first dose of study drug.)
• Concurrent serious uncontrolled or unresolved medical condition, such as infection, limiting protocol compliance or exposing the subject to unacceptable risk
• Positive serology and/or nucleic acid testing (NAT) for human immunodeficiency virus (HIV), active hepatitis B virus (HBV) infection or carrier status for HBV, active hepatitis C virus (HCV) infection
• For Part 1: Positive serology for syphilis or human T cell lymphotrophic virus I/II
• Uncontrolled psychosis, uncontrolled depression or suicide risk, substance dependence, or any other psychiatric condition that may compromise the ability to participate in this trial
• Clinically significant abnormalities of full blood count, renal function, or hepatic function
• Any contraindication to MRI and/or Gd, eg., any object that is reactive to strong static magnetic, pulsed-gradient fields including any metallic fragments or foreign body (eg, aneurysm clip[s], pacemakers, electronic implants, shunts)
• Any history of cancer (as exceptions, successfully treated non-melanoma skin cancer or carcinoma in situ of the cervix with a < 5% chance of recurrence within 12 months of providing informed consent are allowed.)
• Prior therapy with corticosteroids (within 2 weeks before Cycle 1 Day 1)
• Prior therapy (30 days) B-cell depleting agent (eg, anti-CD20 agents such as ocrelizumab); participant must be progressing despite therapy to be eligible
• For Part 1: Prior therapy (6 half-lives or 30 days whichever is longer) with cladribine, glatiramer acetate, interferon ß, dimethyl fumarate, methotrexate, azathioprine, cyclosporine, fingolimod, natalizumab, teriflunomide, mitoxantrone, cyclophosphamide, any other immunosuppressant or cytotoxic therapy (other than steroids), antithymocyte globulin or similar anti-T-cell antibody therapy, or any other investigational product
• For Part 1: Any previous treatment with alemtuzumab, ablative stem cell transplant, or EBV T-cell therapy
• For Part 2: Prior therapy (6 half-lives or 30 days whichever is longer) with IV immunoglobin, plasmapheresis, Bruton's tyrosine kinase inhibitors, all sphingosine 1-phosphate receptor modulators (eg, fingolimod), glatiramer acetate, interferon ß, nuclear factor (erythroid-derived 2)-like 2 (Nrf2) activators (eg, dimethyl fumarate), methotrexate, azathioprine, cyclosporine, natalizumab, teriflunomide, mitoxantrone, cyclophosphamide, any other immunosuppressant or cytotoxic therapy (other than steroids), antithymocyte globulin or similar anti-T-cell antibody therapy, or any other investigational product
• For Part 2: Any previous treatment with cladribine, alemtuzumab, ablative stem cell transplant, or EBV T-cell therapy
• Unresolved reactions from previous therapies that may, in the investigator's opinion, impact the safety of the participant or the conduct of this study
• Unwilling to use protocol specified contraceptive methods
• Women who are breastfeeding
• Pregnancy
• Inability or unwillingness to comply with study procedures

Related Conditions & MeSH terms

• Multiple Sclerosis
• Multiple Sclerosis, Chronic Progressive
• Primary Progressive Multiple Sclerosis
• Sclerosis
• Secondary Progressive Multiple Sclerosis

Intervention

Biological:
• ATA188
ATA188 is being investigated as an off-the-shelf, allogeneic T-cell immunotherapy for the treatment of EBV+ progressive multiple sclerosis.

Drug:
• Placebo
Placebo matching to ATA188

Locations

Country	Name	City	State
Australia	Royal Brisbane and Women's Hospital	Brisbane	Queensland
Australia	Liverpool Hospital	Liverpool	New South Wales
Australia	Griffith University, School of Medicine	Southport	Queensland
Canada	Fraser Health Multiple Sclerosis Clinic	Burnaby	British Columbia
Canada	Recherche Sepmus Inc.	Greenfield Park	Quebec
Canada	Unity Health Toronto/St. Michael's Hospital	Toronto	Ontario
United States	Dent Neurologic Institute	Amherst	New York
United States	University of Colorado	Aurora	Colorado
United States	Advanced Neurology	Fort Collins	Colorado
United States	Fort Wayne Neurological Center	Fort Wayne	Indiana
United States	Advanced Neurosciences Institute ANI - Franklin	Franklin	Tennessee
United States	Premier Neurology P.C.	Greer	South Carolina
United States	The University of Texas Health Science Center at Houston	Houston	Texas
United States	University of Kansas Medical Center KUMC - Multiple Sclerosis MS Center	Kansas City	Kansas
United States	University of California, San Diego	La Jolla	California
United States	Kaiser Permanente MS Clinic Los Angeles	Los Angeles	California
United States	Neurology Associates, PA-Maitland	Maitland	Florida
United States	Medical College of Wisconsin	Milwaukee	Wisconsin
United States	PMG Research of Piedmont Healthcare	Mooresville	North Carolina
United States	Vanderbilt Comprehensive Multiple Sclerosis Center	Nashville	Tennessee
United States	Ochsner Clinic Foundation	New Orleans	Louisiana
United States	Columbia University Medical Center-The Neurological Institute of New York	New York	New York
United States	Stanford University	Palo Alto	California
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Rochester Medical Center - URMC	Rochester	New York
United States	Washington University in St. Louis	Saint Louis	Missouri
United States	University of California San Francisco	San Francisco	California
United States	Inland Northwest Research LLC	Spokane	Washington
United States	University of South Florida, Morsani College of Medicine	Tampa	Florida
United States	MS Center of Greater Washington	Vienna	Virginia
United States	Dragonfly Research	Wellesley	Massachusetts

Sponsors (1)

Lead Sponsor	Collaborator
Atara Biotherapeutics

Countries where clinical trial is conducted

United States,  Australia,  Canada, 

References & Publications (2)

Pender MP, Csurhes PA, Burrows JM, Burrows SR. Defective T-cell control of Epstein-Barr virus infection in multiple sclerosis. Clin Transl Immunology. 2017 Jan 20;6(1):e126. doi: 10.1038/cti.2016.87. eCollection 2017 Jan. Erratum In: Clin Transl Immunology. 2017 Jun 16;6(6):e147. — View Citation

Pender MP, Csurhes PA, Smith C, Beagley L, Hooper KD, Raj M, Coulthard A, Burrows SR, Khanna R. Epstein-Barr virus-specific adoptive immunotherapy for progressive multiple sclerosis. Mult Scler. 2014 Oct;20(11):1541-4. doi: 10.1177/1352458514521888. Epub 2014 Feb 3. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Change from baseline in cervical spinal cord volume on MRI scans		At 12 months after the first dose of study drug
Other	Change from baseline in whole brain volume on MRI scans		At 12 months after the first dose of study drug
Other	Change from baseline in number of Gd-enhancing and new or enlarging T2 lesions on brain MRI scans		At 12 months after the first dose of study drug
Other	Change from baseline in IgG production		At 12 months after the first dose of study drug
Primary	Part 1: Incidence of adverse events		At 12 months after the first dose of study drug
Primary	Part 1: Incidence of clinically significant changes in laboratory tests, electrocardiograms (ECGs), and vital signs		At 12 months after the first dose of study drug
Primary	Part 1: Recommended Part 2 dose of ATA188 monotherapy		Day 1 to Day 35 of Cycle 1 for each participant in dose escalation part (approximately 1 year)
Primary	Part 2: Percentage of participants with confirmed expanded disability status scale (EDSS) improvement at 12 months		At 12 months after the first dose of study drug
Secondary	Part 1: Change from baseline in EDSS score		At 12 months after the first dose of study drug
Secondary	Part 2: Percentage of participants with confirmed EDSS improvement at 15 months		At 15 months after the first dose of study drug
Secondary	Part 2: Percentage of participants with sustained disability improvement (SDI; ie, confirmed EDSS improvement or 20% decrease in timed 25-foot walk [T25W]) at 12 months		At 12 months after the first dose of study drug
Secondary	Part 2: Percentage of participants with SDI at 15 months		At 15 months after the first dose of study drug
Secondary	Part 2: Change from baseline in immunoglobulin G (IgG) index		At 9 months after the first dose of study drug